The compound 2-amino-4,5,6,7-tetrahydro-6-(n-propylamino)benzothiazole is a synthetic aminobenzothiazole derivative whose (6S) enantiomer, commonly known as pramipexole and commercially available under the Mirapex® name, is a potent dopamine agonist and thus mimics the effects of the neurotransmitter, dopamine. The (6R) enantiomer, (R)-(+)-2-amino-4,5,6,7-tetrahydro-6-(n-propylamino)benzothiazole, or “dexpramipexole,” is an effective mitochondria-targeted neuroprotectant that exhibits excellent anti-oxidative properties, and is currently undergoing clinical development for the treatment of amyotrophic lateral sclerosis (ALS).
Synthetic procedures to produce pramipexole/dexpramipexole have been described in patent and non-patent literature. For example, one synthetic process for the preparation of pramipexole is accomplished via reductive amination of propanal with 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. Another preparation of pramipexole and dexpramipexole has also been described, where propionic anhydride and 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole are combined to form the amide intermediate, 2-amino-6-propanoylamino-4,5,6,7-tetrahydrobenzothiazole, which is then reduced to pramipexole/dexpramipexole. Unfortunately, the syntheses described above are not suitable for industrial scale preparation as the hydride reducing reagents involved are inherently dangerous and often toxic.
As described in the literature, racemic 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole can be enantiomerically purified by selective crystallization of the acid addition salt using an optically active acid, such as tartaric acid, followed by neutralization to the free, enantiomerically enriched diamine product. However, this method has limitations as to the optical purity of the resulting 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole product, with typical maximum optical purities of about 98%-99% ee.
Described herein is an improved synthesis of dexpramipexole using a procedure which includes direct alkylation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with n-propyl p-toluenesulfonate, followed by the formation of the dihydrochloride salt of dexpramipexole. The methods described herein provide increased yield and chemical purity as well as increased enantiomeric purity of the product. Additionally, the methods described herein provide a process which can be used on an industrial scale.